A randomized phase III study to compare Bortezomib, Melphalan, Prednisone (VMP) with High Dose Melphalan followed by Bortezomib, Lenalidomide, Dexamethasone (VRD) consolidation and Lenalidomide maintenance in patients with newly diagnosed multiple myeloma

Study scheme

Legend

VCD . Bortezomib, Cyclophosphamide, Dexamethasone

RIC. Restrict

SCT. Stem Cell Transplantation

VMP Bortezomib, Melphalan, Prednisone

HDM. High Dose Melphalan

VRD. Bortezomib, Lenalidomide, Dexamethasone

Study Objectives

Primary study objectives include

• Comparison of Bortezomib, Melphalan, Prednisone (VMP) with High Dose Melphalan followed autologous stem cell transplantation (ASCT).
• Comparison of Bortezomib, Lenalidomide, Dexamethasone (VRD) as consolidation versus no consolidation.
• Comparison of single versus tandem high dose Melphalan with ASCT.
• To assess the efficacy of VMP versus high-dose therapy (HDT) and stem cell transplantation in patients with previously untreated multiple myeloma, as measured by the progression free survival.
• To evaluate the effect of consolidation with VRD followed by Lenalidomide maintenance with no consolidation but Lenalidomide maintenance alone on progression free survival.
• To compare VMP versus single HDT+ ASCT; or VMP versus tandem HDT + ASCT; or single versus tandem HDT + ASCT.
• To compare overall response rate and CR + VGPR (complete and very good partial response) after induction therapy, after VMP or HDT, after consolidation and during maintenance.
• To evaluate overall survival.
• To assess safety and toxicity.
• To assess the prognostic value of risk factors at diagnosis.
• To analyze the prognostic value of myeloma gene expression profiles on the overall response on induction of all patients and of patients treated in the different randomization arms.
• To assess quality of life.

Participation conditions

Inclusion criteria

• Patients with a confirmed diagnosis of symptomatic multiple myeloma stage I to III according to the International Staging System ISS, i.e. at least one of the CRAB criteria should be present;
• Measurable disease as defined by the presence of M-protein in serum or urine (serum proteïn 10 g/l or urine M-proteïn > 200 mg/24 hours or abnormal FLC ratio with involved free light chain (FLC) > 100 mg/l) or proven plasmacytoma by biopsy;
• Age 18-65 years inclusive;
• WHO performance status 0-3 (WHO=3 is allowed only when caused by MM and not by comorbid conditions);
• Negative pregnancy test at inclusion if applicable;
• Written informed consent.

Exclusion criteria

• Known intolerance of Boron;
• Systemic AL amyloidosis;
• Primary Plasmacell Leukemia;
• Non-secretory MM;
• Previous chemotherapy or radiotherapy except local radiotherapy in case of local myeloma progression or corticosteroids maximum 5 days for symptom control;
• Severe cardiac dysfunction (NYHA classification II-IV);
• Significant hepatic dysfunction (serum bilirubin  30 mmol/l or transaminases  2.5 times normal level), unless related to myeloma;
• Patients with GFR <15 ml/min,
• Patients known to be HIV-positive;
• Patients with active, uncontrolled infections;
• Patients with neuropathy, CTC grade 2 or higher; Patients with a history of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
• Patients who are not willing or capable to use adequate contraception during the therapy (all men, all pre-menopausal women;
• Lactating women.

Centre Hospitalier de Luxembourg - CHL (Dr Laurent Plawny)